Major depressive disorder (MDD) is a leading cause of disability in the world. Treatment-Resistant Depression (TRD) causes the majority of MDD's disability. This grant is a randomized, controlled trial of Mindfulness- Based Cognitive Therapy (MBCT) for the TRD population. MBCT is a new technique that has previously been found effective for prevention of relapse in individuals in complete remission and has shown emerging evidence of efficacy in TRD. MBCT is a group-based, 8-week intervention that uses mindfulness meditation as its core therapeutic ingredient. It teaches people to have a different relationship t depressive thoughts and feelings. This study will use an active comparator condition, the Health-Enhancement Program (HEP). We plan to identify 174 patients with TRD. We will then randomly assign patients to two groups: MBCT+TAU (treatment as usual medications) or HEP+TAU. We anticipate 150 patients will complete treatment and undergo follow-up assessments at 6, 9 and 12 months The specific aim of the first phase of study is to determine the acute efficacy of MBCT in reducing depression in adults with TRD. We will also conduct a series of secondary hypotheses and analyses to evaluate MBCT's efficacy in reducing disability and improving quality of life. A second phase of the study will evaluate fMRI findings in 88 participants before and after completing their respective intervention groups. This phase of the study will specifically investigate MBCT effects on the brain's dorsal executive control and ventral affective processing systems. The dorsal executive control system has typically been found to have decreased activations in fMRI studies of depression, while the ventral affective system has been associated with increased activations. The former system will be probed with a working memory task while the latter is investigated with an affect labeling task. We will also obtain resting state analyses pre and post intervention to evaluate change. Our hypothesis is that MBCT specifically strengthens the dorsolateral and ventrolateral prefrontal cortices in task execution as neural mechanisms mediating its emotion regulation in treating depression. These and other brain regions will be investigated in comparison to change in depression severity of MBCT and HEP completers. In the third phase of the study, baseline fMRIs of individuals with TRD will be compared to healthy controls. This will allow for a characterization of functional abnormalities present in TRD, particularly in the dorsal executive control and affective processing brain regions. This component of the study will also yield information on whether treatment that is successful in reducing depression severity is also able to reverse functional brain abnormalities. Finally, this phase will also provide fMRI data about the neural signatures of TRD to help predict who the best candidates for MBCT are. PUBLIC HEALTH RELEVANCE: Major depressive disorder is the most prevalent mental health problem in the world. Strikingly, 70% of individuals with major depressive disorder will fail to remit with adequate initial treatment, thus suffering Treatment Resistant Depression (TRD). This supplement builds on a parent study that is a randomized controlled trial of a new treatment for TRD, Mindfulness-Based Cognitive Therapy (MBCT). This supplement would compare individuals with TRD to healthy controls at baseline, to better characterize functional brain abnormalities in TRD. It would also allow an understanding of whether MBCT reverses these abnormalities. The study may also allow for identification of better predictors of who responds best to MBCT. Since TRD is such a widespread disorder and is responsible for much of the morbidity and mortality of major depressive disorder, this study promises to increase our understanding of both the disorder and a new treatment for it. As such, the study would have a major public health impact.